Epitope-Based T-Cell Therapy for Epithelial Tumors. Because the immune system has the capacity to recognize and in many cases destroy tumor cells, significant efforts are being devoted to the development of immune-based therapies for cancer. Both cytotoxic T lymphocytes (CTL) and helper T lymphocytes (HTL) have been shown to react with antigens expressed by tumor cells and as a result establish protective and therapeutic effects. Since CTL and HTL recognize antigens in the form of peptide complexes with major histocompatibility complex (MHC) surface molecules (HLA in humans), it is necessary to identify the nature of tumor-derived peptides that can elicit T-cell responses capable of inhibiting tumor-cell growth. The overall objective of the proposed study is to identify peptides derived from sequences of several known tumor-associated antigens (TAA) that will be capable of stimulating CTL and HTL against tumor cells. We have selected six TAA that are widely expressed on tumor cells of epithelial origin: MAGE, CEA, HER2, HER3, p53 and FAK. The amino acid sequences of these TAA have been screened for the presence of peptides containing MHC binding motifs. Corresponding peptides will be synthesized and tested for their capacity to elicit in vitro T-cell responses to tumor cells and corresponding TAA as a final proof that they truly represent T-cell epitopes. The ultimate goal of our work is to utilize these tumor-reactive T-cell epitopes to develop immunotherapeutic approaches to treat commonly found epithelial cancers (breast, gastrointestinal and lung). To accomplish this goal, we propose the following specific aims: 1-identify MHC class I-restricted CTL epitopes from TAA commonly found on epithelial cancers; 2-Identify MHC class II-restricted helper T-cell epitopes from TAA commonly found on epithelial cancers; 3.- Increase CTL and T helper immune responses to TAA's by epitope re-engineering. The completion of these aims should facilitate the development of novel broadly applicable T-cell based immune therapies such as epitope-based vaccines and T-cell adoptive therapy for the treatment of frequently encountered tumors.